Medulloblastoma (MB), a rare yet critical pediatric brain tumor, is divided into 4 molecular subgroups (WNT, SHH, Group 3, Group 4), each with distinct genetic profiles. Despite diagnostic and therapeutic advances, neurotoxicity from standard treatments (resection, radiotherapy, chemotherapy) and the need for long-term care remain challenges. CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib), approved for breast cancer, show potential in other tumors, but their efficacy in MB is unclear. Treatment resistance is a concern. This project aims to identify genetic markers of sensitivity to CDK4/6 inhibitors in MB, to improve therapies and overcome resistance.
All patients affected by Medulloblastoma operated on at the Pediatric Neurosurgery Unit during their pediatric age will be elected to take part to the study
None
Parallel
CDK4/6 Inhibitor (Palbociclib, Ribociclib, Abemaciclib)
DrugEvaluation of the response to CDK4/6 inhibitors (Palbociclib, Ribociclib, Abemaciclib) on selected Medulloblastoma (MB) patient-derived organoids (PDOs).
Clarify the molecular mechanisms underlying the acquisition of resistance to CDK4/6i in MB.
Genetic characterization of PDOs derived from patients with medulloblastoma (MB). Measurement: Analysis of the mutational status of over 500 genes using TSO-500 sequencing, comparing the genetic profiles of PDOs with those of primary tumors.
Clarify the molecular mechanisms underlying the acquisition of resistance to CDK4/6i in MB.
Assessment of changes in cell proliferation in patient-derived organoids (PDOs) from medulloblastoma (MB) treated with CDK4/6 inhibitors compared to untreated controls. Measurement: Quantified by cell counting assays.
Clarify the molecular mechanisms underlying the acquisition of resistance to CDK4/6 inhibitors in medulloblastoma (MB).
Histological characterization of PDOs derived from patients with medulloblastoma (MB). Measurement: Evaluation of the expression of MB-specific histological markers by immunohistochemistry, comparing expression patterns between PDOs and primary tumors.
Clarify the molecular mechanisms underlying the acquisition of resistance to CDK4/6i in MB.
Assessment of changes in cell survival in patient-derived organoids (PDOs) from medulloblastoma (MB) treated with CDK4/6 inhibitors compared to untreated controls. Measurement: Quantified by cell viability assays.
CDK4/6 inhibitor-resistant clones
Proportion of medulloblastoma PDOs with maintained proliferation following exposure to CDK4/6 inhibitors, as assessed by cell viability assays.
transcriptomic analysis
Gene expression differences among medulloblastoma PDOs that are sensitive, primarily resistant, or secondarily resistant to CDK4/6 inhibitors.
Evaluate new therapeutic strategies
Reduction in cell viability of CDK4/6 inhibitor-resistant medulloblastoma PDOs following treatment with novel therapeutic combinations
Quantification of fluorescence intensity for tumor marker detection using synthetic DNA nanoswitches in histological sections from medulloblastoma patients and patient-derived organoids (PDOs)
Fluorescence intensity corresponding to specific tumor markers detected by synthetic DNA nanoswitches will be measured in histological sections of medulloblastoma patient tumors and patient-derived organoids (PDOs), using standardized fluorescence microscopy protocols. Measurement Tool: Fluorescence microscopy analysis (mean fluorescence intensity per sample). Unit of Measure: Mean fluorescence intensity (arbitrary fluorescence units, AFU).
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Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Lead sponsor
University of Rome Tor Vergata
Collaborator
Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
Collaborator
Università degli Studi di Enna Kore
Collaborator
